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Carcinogenesis Advance Access originally published online on February 6, 2008
Carcinogenesis 2008 29(6):1164-1169; doi:10.1093/carcin/bgn020
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers

Shanbeh Zienolddiny*,1,{dagger}, Daniele Campa2,{dagger}, Helge Lind1, David Ryberg1, Vidar Skaug1, Lodve B. Stangeland3, Federico Canzian4 and Aage Haugen1

1 Section of Toxicology, Department of Biological and Chemical Work Environment, National Institute of Occupational Health N-0033, Oslo, Norway
2 Department of Biology, University of Pisa, 56126 Pisa, Italy
3 Haukeland University Hospital, N-5021 Bergen, Norway
4 Department of Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

* To whom correspondence should be addressed. Tel: +47 23195284; Fax: +47 23195203; Email: shan.zienolddiny{at}stami.no

Lung cancer is a leading cause of cancer mortality worldwide with smoking and occupational exposure to carcinogenic compounds as the major risk factors. Susceptibility to lung cancer is affected by existence of polymorphic genes controlling the levels of metabolic activation and detoxification of carcinogens. We have investigated 105 single nucleotide polymorphisms (SNPs) in 31 genes from the phase I and phase II metabolism genes and antioxidant defense genes for association with the risk of non-small cell lung cancer (NSCLC) in a Norwegian population-based study. Our results indicate that several SNPs in the phase I genes, CYP1B1, CYP2D6, CYP2E1 and CYP3A4, are associated with the risk of NSCLC. Moreover, significant associations with multiple SNPs in the phase II genes ALDH2, COMT, EPHX1, SOD2, NAT1, NAT2, GSTM3, GSTP1, GSTT2 and MPO were also found. We prioritized our findings by use of two different recently developed Bayesian statistical tools, employing conservative prior probabilities of association. When we corrected for multiple testing using these statistical tools, three novel associations of NSCLC risk with SNPs in the CYP1B1 (Arg48Gly), COMT (Val158Met) and GSTT2 (Met139Ile) genes were found noteworthy. However, only four of the previously reported associations with polymorphisms in the GSTP1 (Ala14Val), SOD2 (Val16Ala), EPHX1 (His139Arg) genes and the NAT1 fast acetylator phenotype remained significantly associated with lung cancer.

Abbreviations: BFDP, Bayesian false-discovery probability; COMT, catechol-O-methyltransferase; FPRP, false-positive report probability; GST, glutathione S-transferase; NAT, N-acetyltransferases; NSCLC, non-small cell lung cancer; OR, odds ratio; SNP, single nucleotide polymorphism

{dagger} These authors contributed equally to the manuscript.

Received September 12, 2007; revised December 21, 2007; accepted January 14, 2008.


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